mTOR is a serine/threonine kinase and has been identified as a regulator of protein synthesis as well as cell growth and proliferation. Also, mTOR has been shown to regulate the response of tumor cells to nutrients and growth factors as well as the ability of tumors to promote angiogenesis. Thus, inhibitors of mTOR activity are being actively studied as potential anti-proliferative agents. Currently inhibitors of mTOR are approved for immunosuppression and cancer treatment.
Inhibition of mTOR function by small molecules results in a loss of transmission of upstream activating signals (i.e., from growth factor receptors) to downstream effectors of cell growth. Rapamycin, an inhibitor of mTOR, inhibits proliferation or growth of cells derived from a range of tissue types such as smooth muscle and T-cells as well as cells derived from a diverse range of tumor types including rhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma and breast and prostate carcinoma. Moreover, rapamycin and its derivatives have shown the ability to potentiate the cytotoxicity of a number of common cancer chemotherapies including cisplatin, camptothecin and doxorubicin.
It has been shown that mTOR functions in two distinct complexes (mTORC1 and mTORC2). Rapamycin primarily inhibits the mTORC1 complex while largely sparing mTORC2 activity. Thus, one strategy is to identify compounds that are capable of inhibiting mTORC1 and mTORC2 mediated activity in the cell. The compounds of the present invention are such inhibitors of mTOR and are useful to treat disorders associated with mTOR.
In addition, mTOR Complex1-S6K1 integratesvarious extrinsic signals that regulate cell growth and metabolism. Experiments with rapamycin provided a link between mTOR Complex1-S6K1 and adipogenesis. Also it has been demonstrated that S6K1-deficient mice are protected from diet and age induced obesity.
Certain inhibitors of PI3K are disclosed in WO2006/005915. Certain inhibitors of mTOR and/or PI3K are disclosed in WO 2008/023180.